Tuesday, December 29, 2009

The Body Fat Setpoint

One pound of human fat contains about 3,500 calories. That represents roughly 40 slices of toast. So if you were to eat one extra slice of toast every day, you would gain just under a pound of fat per month. Conversely, if you were to eat one fewer slice per day, you'd lose a pound a month. Right? Not quite.

How is it that most peoples' body fat mass stays relatively stable over long periods of time, when an imbalance of as little as 5% of calories should lead to rapid changes in weight? Is it because we do complicated calculations in our heads every day, factoring in basal metabolic rate and exercise, to make sure our energy intake precisely matches expenditure? Of course not. We're gifted with a sophisticated system of hormones and brain regions that do the "calculations" for us unconsciously*.

When it's working properly, this system precisely matches energy intake to expenditure, ensuring a stable and healthy fat mass. It does this by controlling food seeking behaviors, feelings of fullness and even energy expenditure by heat production and physical movements. If you eat a little bit more than usual at a meal, a properly functioning system will say "let's eat a little bit less next time, and perhaps also burn some of it off." This is one reason why animals in their natural habitat are nearly always at an appropriate weight, barring starvation. The only time wild animals are overweight enough to significantly compromise physical performance is when it serves an important purpose, such as preparing for hibernation.

I recently came across a classic study that illustrates these principles nicely in humans, titled "Metabolic Response to Experimental Overfeeding in Lean and Overweight Healthy Volunteers", by Dr. Erik O. Diaz and colleagues (1). They overfed lean and modestly overweight volunteers 50% more calories than they naturally consume, under controlled conditions where the investigators could be confident of food intake. Macronutrient composition was 12-42-46 % protein-fat-carbohydrate.

After 6 weeks of massive overfeeding, both lean and overweight subjects gained an average of 10 lb (4.6 kg) of fat mass and 6.6 lb (3 kg) of lean mass. Consistent with what one would expect if the body were trying to burn off excess calories and return to baseline fat mass, the metabolic rate and body heat production of the subjects increased.

Following overfeeding, subjects were allowed to eat however much they wanted for 6 weeks. Both lean and overweight volunteers promptly lost 6.2 of the 10 lb they had gained in fat mass (61% of fat gained), and 1.5 of the 6.6 lb they had gained in lean mass (23%). Here is a graph showing changes in fat mass for each individual that completed the study:

We don't know if they would have lost the remaining fat mass in the following weeks because they were only followed for 6 weeks after overfeeding, although it did appear that they were reaching a plateau slightly above their original body weight. Thus, nearly all subjects "defended" their original body fat mass irrespective of their starting point. Underfeeding studies have shown the same phenomenon: whether lean or overweight, people tend to return to their original fat mass after underfeeding is over. Again, this supports the idea that the body has a body fat mass "set point" that it attempts to defend against changes in either direction. It's one of many systems in the body that attempt to maintain homeostasis.

OK, so why do we care?

We care because this has some very important implications for human obesity. With such a system in place to keep body fat mass in a narrow range, a major departure from that range implies that the system isn't functioning correctly. In other words, obesity has to involve a defect in the system that regulates body fat, because a properly functioning system would not have allowed that degree of fat gain in the first place.

So yes, we are overweight because we eat too many calories relative to energy expended. But why are we eating too many calories? There are a number of reasons, but one reason is that the system that should be defending a low fat mass is now defending a high fat mass. Therefore, the ideal solution is not simply to restrict calories, or burn more calories through exercise, but to try to work with the system that decides what fat mass to 'defend'. Restricting calories isn't necessarily a good solution because the body will attempt to defend its setpoint, whether high or low, by increasing hunger and decreasing its metabolic rate. That's why low-calorie diets, and most diets in general, typically fail in the long term. Restricting calories works for fat loss, but most people find it miserable to fight hunger every day.

This raises two questions:

What caused the system to defend a high fat mass?

Is it possible to modify the fat mass setpoint, and how would one go about it?

Given the fact that body fat mass is much higher in many affluent nations than it has ever been in human history, the increase must be due to factors that have changed in modern times. I can only speculate what these factors may be, because research has not identified them to my knowledge, at least not in humans. But I have my guesses. I'll expand on this in the next post.

* The hormone leptin and the hypothalamus are the ringleaders, although there are many other elements involved, such as several gut-derived peptides, insulin, and a number of other brain regions.

I was just discussing this with my husband, as we have some obese family members and it baffles me when I see pictures of them from many years ago and they were thin!not at all overweight, much less obese. It seems that something... perhaps you will allude to this in your next post, "makes" them over-eat constantly. I don't believe it to be within their control psychologically. It truly seems like some hormonal, psysiological urge is in control. Because really, who would want to be obese if they could truly help it?

It's worth pointing out that wild animals are in their natural environments and their intake is regulated somewhat by the availability of food. When animals do not have to hunt or forage, they do tend to get chubby. Any owner of a labrador retriever can back this up. A strict raw-food, no-grain diet helps but it doesn't fix the chubby completely. Not all dogs are adversely affected by cheap, easy food - in the same way that not all humans get fat in the presence of readily available calories - but a good portion do.

We're not in the environment for which we're evolved, that's the problem. Yes, there's a complex system of hormones and whatnot that regulate appetite and intake and metabolic rate, but explaining human obesity in those terms is like putting a car underwater and explaining that it doesn't run because the spark plugs are gapped wrong for the new atmosphere. True, but...?

What about 'tricking' your metabolism? I read in a bodybuilding book that they use a technique where they consume less calories than usual for 3-4 days, then consume more than the usual amount of calories for 1 day to prevent the body from lowering the base metabolic rate.

I would have expected the overweight group in the trial to not be as able to defend their set point as the originally lean group. The fact that they were able to get back to their set point means that they were a group of overweight individuals with properly functioning bodies. The body must really be out of whack then to be considered malfunctioning.Interesting stuff

Don't forget there are also 10 times as much intestinal bacterial in a human being as cells in the host. They determine a large amount of how food we eat gets processed, where it goes and what metabolic rate and fat ratios the host should maintain.

One of the problems of modern civilization, besides the SAD, is liberal use of antibiotics and over-sanitizing of our food, which disregulates this ecology in our bodies and allows pathogenic bacteria to gain the upper hand in our guts. This could manifest itself as inflammation and increased adiposity.

On another note, it's interesting that after overfeeding the subjects lost 61% of the new fat mass they gained, but only 23% of the new muscle mass. So we're left with roughly 4 lbs of extra fat and 5 lbs of extra muscle.

Muscle mass is active tissue which raises resting metabolism, so it immediately would have an effect on fat and body composition. I don't know how long it takes for each to come back to normal, but in the context of a paleo-style low-carb diet, the extra lean tissue may outlast the fat.

Which means overfeeding and underfeeding could be a great way to gain lean mass and burn fat over time! This could be why IF and compressed eating windows seem to work so well, as they are basically a mini version of your chart.

As a postscript to the above, here's a study by Gilbert Forbes showing that the ratio of lean body mass to fat that one gains on overfeeding are different depending on how much body fat you have to begin with. I guess there's no such thing as a free lunch when trying to recomp you body sitting on your butt...

Lyle mcdonald has spent a great deal of time looking into setpoints and hormones, and has written quite a bit about it both on his blog and in his books. However, he is a "calorie is a calorie" guy, I just don't understand why. He's also easily insulted and lashes out at people with whom he disagrees. *shrug* anyway, I'm very curious where Stephen is going on this topic. I have my own opinion based on Stephen and Peters writing about what causes obesity, namely high insulin levels caused by an insulin resistant liver which inhibits lipolysis. Do people really experience major hunger or food preoccupation when losing weight after fixing their liver?

This is a purely anecdotal observation, but I have noticed that there appears to be a "culture of snacking" that emerged in the United States sometime in the past 20 years.

I have heard the toxic environement theory of obesity ad nauseum, but why is it when I travel to Japan everybody is thin? You can food anywhere over there. Vending machines and restaurants a plenty.

We had plenty of access to refrigerators full of food 25 years ago in America, but people were far thinner. One of my most vivid memories from childhood in the very early 1980s was father slapping my hand anytime I tried to go for the cookie jar after eating dinner. And absolutely no snacking was allowed before dinner per the age old advice that it would "ruin my dinner."

How does all of this snacking affect insulin and leptin levels? It must have an effect.

Parents today keep reinforcing this behavior with their children. Before dispatching children to play, I cannot help but notice that most mothers utter "but he/she needs a snack first!" In 1980, my mother just told me to get the hell out of the house.

I think this culture of snacking, which prevents any sort of fast, especially after dinner, has been detrimental to our waistlines.

What do you think about the concept of alternative day diets where one eats a very low intake one day and an intake higher than maintenance the next? The science behind it rests on a single mouse study, (yeah, I know) but the claimis that it achieves the same effects as calorie restriction without metabolic slow down.

I've heard interesting reports that this diet can be very effective from people who seem reliable.

Jenny, I have been doing a lot of research into alternate day fasting as well. I have had such terrible long-term experiences with low-calorie diets that I have a lot of trouble accepting that they are an acceptable way to lose weight. So the idea of skipping meals did not appeal to me at first. However, Dr. McBride from the GAPS diet suggests not eating anything until after 10am because your body is still detoxing until that time. After hearing that, I ran across some information about alternate day fasting, and how the point is to let your body detox, restore insulin sensitivity, and devote energy to healing on your "off" days. You still feed your body plenty of calories on your "on" days, so starvation is not an issue if you are eating quality foods.

While I've found some helpful information about ADF online, mostly I keep running across people who are combining ADF with low-calorie diets, low-fat diet, or just junk food diets! It's hard to determine reliable results when so many people who try ADF appear to be mislead about what's healthy.

In any case, I just started alternate day fasting in an attempt to "reset my fat setpoint," or something along those lines. With healthy, nourishing foods of course. So we'll see what the results are!

From my self-studies, I've noticed that eating a fixed amount of energy (about 50% deficit from maintenance) spread over 8 hours (12-20) will cause sleep issues and make me ravenous, obsessing about food, after about a week. Seems to be a cut-off point.

However, if I cram in all that food in a 3-hour eating window (18-21), I don't experience the same detrimental effects. There seems to be a different response, over time, to the signal of "eat until satisfied, but not more" (two meals a day) compared to "eat until stuffed, and then some" (basically a three-hour sitting) -- despite same caloric content.

Roberts' claim sounds absolutely idiotic. There is quite a difference between losing weight and actually being healthy. Where are his graphs of lipid profile measures? Or is this diet only for the short-sighted, who prefer losing their fat rolls to living a long, healthy life?

This is a great post. I suspect you will reiterate the main toxic neolithic food agents (sugar, white flour, veg oils) in addition to mentioning a few more: perhaps vitamin and mineral deficiencies, and environmental toxins.

I recently discovered that our local school has water so high in flouride that it has to be trucked in or the kids get brown spots on their teeth. It is also high in uranium. (!?!) (We live in the Front Range mtns.) To be honest, we live in a fairly pristine area, so it never occurred to me that my water could be a problem. It tastes amazing. I've been wondering if high levels of flouride in our water haven't been hurting my ability to lose weight by depressing my thyroid. So I'm going to stop drinking it.

I definitely haven't been as diligent this holiday season as I need to be, but I had a 5 pound weight gain on just a few days of minor indiscretion. That's ridiculous. I've noticed it's much, much more difficult to maintain a healthy weight, even on low carb, than it was for me before I moved here.

I'm not saying it's all the water, only that I suspect it doesn't help. My TSH is fine but my temperatures are sometimes depressed. Maybe all those years of slamming my body with vegetable oil fried doughnuts caught up with me.

I bought "Mastering Leptin" by Byron Richards about a year ago (must go minimum 3 hours w/o eating on a regular basis to restore leptin signaling), and read "Good Calories Bad Calories" by Gary Taubes last summer (huge increase in refined grains and sugar is by far the primary cause of the obesity epidemic). I have now taken 4 inches off my waist (after being stuck at 40 for over 10 yrs on a variety of diet and exercise plans); it actually becomes kind of easy once you have the right knowledge. So I think the body's different hormonal response to different foods is the key.

Stephan, I am glad that you posted this and would like to invite your readers to expand on the ideas in this post by looking at another blog, 180 Degree Health (I've seen you comment there!). Matt Stone has adopted the idea that people have developed depressed metabolisms from years of poor eating, and that a way of overcoming that is by periods of overeating. Our bodies should naturally want to avoid getting overfat, but our hormonal control of that has become compromised by an eating style that prevents the body from operating normally and avoiding excess fat accumulation and poor health.

If you can tolerate a little weight gain, overeating can be extremely therapeutic. Once your metabolism kicks in, you can really feel the difference. Cold hands become warm as circulation improves, bowel movements increase to 3 or more times per day, the symptoms of hypoglycemia vanish even in the presence of hunger, skin clears up, immunity improves, and a general feeling of wellness becomes always prevalent.

It seems that periods of high caloric intake improves thyroid function, improves insulin sensitivity and allows overtaxed adrenals to rest and recover. Paleo and low carb eating styles seem to help greatly with insulin control, but at 180 Degree Health the idea is to overcome the problem, not run from it. Even Dr. Atkins admitted that his diet would lead to hypothyroidism.

Many people are reporting great results on an high calorie diet after trying various other diets that worked for a while but did not solve the underlying problem of a low metabolism. I have been eating 4000 kcals+ per day for about 2.5 months and have gained 6 lbs, but the feeling of health that I currently have is far superior to what a year and a half of low carb and paleo eating produced. Just something to check out, it is an interesting idea that has not been explored much, and people do seem to be finding that it is effective to improving sluggish metabolisms.

Of course, when overeating, only use quality foods; avoid nutritionally devoid foods such as processed grains, sugar, and omega-6 vegetable oils.

hmmm well if people had common sense they would understand that as human beings the majority of people diets are not even food. if your past diet has f-ed up your hormones, that sucks, and losing weight will be hard. if you obese and hormones function, eat REAL food, aka food humans are supposed to eat, and there is no reason to overeat or not lose weight.

this just boggles my mind how obese people sit around dumbfounded over a bag of pretzels(fat free!) and wonder what the problem is while throwing back a handful of pills to give into the diet industries capitalistic approach to treat the symptoms and not cure diddly squat

the right diet and good high fat nutrion will treat the brain problems, the chemical imabalnces and all the psychological issues...IMO

Comment inline with PaleoRD, after 12month Lowcarb, which 9months were very low carb I am following 180health. I am 3 months on overeating 'whole' foods, 4 to 5 meals a day always mixed carb/protein/fat (3K to 4K cals/day) and walking is only excerise.

Insulin and cortisol start to balance out, adrenals get a rest, and thyroid starts to rev up.

I have gained 10lbs of lean mass and fat. Once hormones balance and temps are running at 98.6 during the day, body will burn off fat that is not needed, in theory! This can happen quick for some, or take alot longer for some, which may include greater weight gains and weight loss.

Regarding 180, I've tried it. Put on fat. Tried low carb without calorie restriction, lost fat. I wish I were part of the large minority of people who can eat carbs and be lean, but I'm stuck with the majority. I've never had a broken metabolism or been overweight by most standards, it's just 1. I'm leaner on low carb, and 2. I'm scared about the evidence that carbs are bad for you, and there is a lot of it, buttressed by the fact that there are so many skinny ravenous glucose eaters getting angioplasties at 60. I love carbs, but I don't want to be fat or unhealthy.

As far as the Seth Roberts appraoch goes, FWIW, I've done his Shangri-La routine and it worked great. Slowly but steadily I lost around 15 pounds, and I wasn't fat to begin with. Easy as pie, by the way -- all I did was ingest around three-four tablespoons of oil once a day, an hour in both directions from any other food. Result: I ate a lot less than I usually do, and had no desire to snack, crunch or much thru the day.

I'm not at all sure I see any reason to buy a lot of Seth's theories as to why the approach works for some people. For me, it was all about appetite suppression. The oil you ingest represents some calories, but you wind up eating much less than usual, without being bugged by it, so the total ingestion is less.

It's quite funny when the appetite-suppression kicks in. (Took about four or five days in my case.) I remember at one meal reaching out for my usual seconds ... and then my hand came back empty. I stared at it. What had happened? What had happened was that my body had decided I'd had enough. Cool.

I've just begun Seth Robert's Shangri La diet after I could not lose the last pounds I wanted with Low Carbing. The appetite suppression is amazing. I'm down to 1 (evening)meal/day and even that meal is just a regular sized one. Seth is onto something but the science behind it it flimsy. Maybe Stephan can add some science ?

Seriously, this is just more nonsense like the people who tell you that you can't skip breakfast, i.e., you must eat even if you're not hungry.

Certainly, most people feel like pigging out, me included, and when I do, then I do even if it's midnight. But force feeding yourself when you're not hungry is just nonsense in my view.

The one caveat I'd say is intermittent fasting. Due to the unnatural ease with which we can store and have food at our fingertips, it's a good idea to model scarcity intermittently. This is completely different from turning our evolution on its head by subjecting your body to something it was not designed for: chronic gluttony.

Lots of good discussion in the comments...weight loss will always get people interested enough to say something. The control of fat is, unfortunately, a very common quest.

The issue for some, I see (and myself included) is that the fat mass percentage that our bodies want to defend - no matter what macronutrient ratio we follow - feels and looks "fat" to us.

It would be great if my body would defend 10% bodyfat, but it seems to want to defend double that or more. Genetically, I can see that this runs in my family, but it doesn't make me like it any more. At some point, we start to cross the line into body image...but we keep trying different stuff anyway.

I really have to agree with Spughy (4th comment). I highly suspect that I would not carry as much fat as I do if I lived a year with the Kadza hunter-gatherers in Africa. In my quest to "eat real food to fullness whenever I got hungry" I would be working quite a bit harder than walking down to the supermarket and I would be eating a lot less than I wanted when all the sharing was done with the other tribe members.

A question for Stephan: Why does our body want to have a couple dozen pounds (or more) of extra fat anyway? Our muscle glycogen gives us the "run from the tiger" burst of speed. So the fat mass must have evolved for enduring through long periods of starvation. And I mean really long, because there is a lot of energy in those pounds of fat.

Which would seem to support the notion that man in his natural environment had a lot of starvation to endure. If food was always abundant, why evolve the need to store more than just enough fat to make it to the next meal?

One might argue that for some populations, subcutaneous fat evolved to provide more warmth. Seems to make sense...but again, if food were always abundant, then evolving a higher metabolism to maintain a higher body temperature would seem to be more efficient. So we come back to the starvation theory I suppose.

I know that for me, hunger is not to be trusted at all as an indicator that my body really needs to eat anything. This applies no matter what eating plan I follow. Better for me to learn to live with it, which kind of sucks, but you get used to it if you do it long enough.

180 doesn't advocate indefinite overfeeding. It's a temporary measure taken to achieve a specific goal, which is a reduction in insulin resistance and a rise in basal metabolism. This is due to both caloric and nutritional superabundance. Eventually, appetite comes to a standstill.

I don't feel like pigging out like Nikoley does, nor do I have "hypometabolism" written all over my puffy, mucin-saturated face. I can now barely eat 3,000 calories per day. My fasting blood sugar is 70 mg/dl. I can eat 2 baked russet potatoes and have a postprandial glucose reading of 75 mg/dl.

But you know, you can do your intermittent fasting and reach a basal body temperature of 96 degrees if you want. Apparently the NY Times thinks that's just 'normal.'

Yes, the overweight people have a setpoint their body is trying to defend as well, it's just higher than that of the lean patients. If there was no setpoint and you ate 10% more calories than you burned, you'd be morbidly obese in just a couple of years. Everyone except the most morbidly obese individuals probably has some setpoint that the body is defending, it's just higher than it should be.

Hi gunther,

Yes, it didn't escape my attention that they hung on to most of the lean mass they built during overfeeding. I think bodybuilders use that technique-- stuff yourself during the off season, even if it makes you chubby, then starve to get lean for competition.

Hi Mark,

I'm with you on the snacking. I'll add soda to the list.

Hi Jenny,

There are actually some human data to support that as well. It could be a useful strategy.

I'm open to the idea that short-term overfeeding could be a useful strategy. I need to see evidence that the fat mass disappears after overfeeding is over though, and that the reported improvements in health are also enduring and more than just anecdotes. Mostly what I've heard is anecdotes of people putting on fat and feeling good, but I'd like to know what happens to these people after the overfeeding is over.

Hi Scott,

I don't think we evolved to have a high fat mass. A lean person has enough fat to live without any food for a solid month. We must have faced some degree of food insecurity, or else we'd have even less fat, but studies of contemporary HGs show that most groups don't starve with any regularity. That said, I think it's possible to be perfectly healthy as a male with 20% body fat, as long as it isn't predominantly visceral.

"I'm open to the idea that short-term overfeeding could be a useful strategy. I need to see evidence that the fat mass disappears after overfeeding is over though, and that the reported improvements in health are also enduring and more than just anecdotes."

Maybe you can organize a study, or do one on rats if you still work at that lab. Try some overeating experiments and see what happens. There are only a few studies that I know about (this one, the prisoner one and the twins).

I agree that scientific studies are good indicators of casual relationships, and eating in excess should be explored precisely because it is the exact opposite of everything else that is recommended now (low fat, high fiber, no saturated fat, no butter, take statins, use sunscreen, reduce salt, eat less meat, use vegetable oil, etc...)

Regarding the bodybuilders, ask them which cycle they would rather be on. Bulking wins by far. This is because androgens are elevated as well. My sex drive was really boosted after overeating. My wife and I were able to conceive within one month of overeating after 4 months of trying. I'm not saying that our diet caused the conception, but something happened!

UndertowThe skin improvement is incredible. I live in dry as hell San Diego and have not used any lotion once this winter. No dryness at all and also no oiliness.

I lost weight and then weighed 120 pounds give or take 5 pounds any time.

My body did not work normally after this weight loss. It behaved as if I were starved. I felt miserable. I was hungry and tired. I could not reproduce.

I did research and hypothesized that the massive weight loss tricked my body into no longer making leptin.

I had my leptin measured. It was 2. This is lower than people who have anorexia nervosa.

I joined a study to get leptin replacement.

The leptin fixed everything. I effortlessly maintain my weight. When I overeat, I barely gain weight, much of it is muscle, and it is very very easy to lose it. This did NOT occur sans leptin. I have tons of energy, I have reproductive cycles, etc. It's pretty fantastic. I take an extremely low dose, much lower than most women given leptin in studies. Even the low dose works quite well.

I am truly leptin deficient, I guess.

Hunger is actually one of the least uncomfortable sensations of being leptin deficient. Depression, coldness, fatigue, blood sugar problems... are all worse. Hunger is the least of your problems when your body is acting like it's starved, really. You just feel like total sh*t.

My theory:I believe that obesity is a scar from severe hyperinsulinemia.

I believe being subject to very high levels of insulin changes the fat tissue (possibly by severe adipocyte hyperplasia) so that the fat tissue can no longer tolerate a normal fat mass (normal / typical amount of fat tissue in kgs). If the native attempts to atrophy the fat tissue via low carbohydrate and low calorie diets, they will find themselves extremely hypoleptinemic. Hypoleptinemia then initiates anti-starvation genetic programs (suppression of HPA/HPO endocrine axes, diabetic-like changes in the liver and peripheral tissues in response to insulin, basically you feel like sh*t physically and emotionally).

The effect of absolute hypoleptinemia on the body ensures the individual either becomes a fat ass again, *or* they go about life insane from starvation symptoms. All sane people will become fat so as to restore leptin levels to an adequate level.

I believe this abnormality in leptin production is CAUSED by being previously exposed to chronic or severe hyperinsulinemia. The hyperinsulinemia damages the fat tissue - possibly by extreme hyperplasia - so that absolute fat mass must be maintained at a high level in order for leptin production to be adequate. Fat mass doesn't make leptin, fat CELLS make leptin... and fat CELLS will only make leptin if they are full.Insulin makes fat cells mature and grow.1 + 1 = 2.High insulin = more fat cells. More fat cells = more minimum fat mass to avoid hypoleptinemia.It's sorta that simple, I think.

If the world were 1/4th as smart as me, obesity wouldn't really be a big issue. Insulin control plus replacement leptin after weight loss... we'd be healthy weight.

Leptin maintenance is all about weight stability/avoiding regain. The only way to fix this problem is by injecting the protein, as if you were a type 1 diabetic. The body which has been damaged by insulin will never make leptin normally again, unless fat mass is high. It's just how it is, unfortunately.

As far as I can see, the only real solution to obesity that has already occurred is replacement leptin (or developing a drug that tricks the fat cells into dying off so that a smaller fat mass is once again acceptable... or a type of virus that perhaps causes higher leptin production, or what not).

Expecting people to reduce insulin to lose weight, and then suffer with starvation symptoms for life, is completely frigging unrealistic and downright cruel.

One of the problems with a binge-and-cut eating program is that it takes so much longer to lose fat than it does to gain it. You may never see the new muscle mass you put on, which would defeat the purpose of the diet.

Though I don't consider bodybuilders healthy, to be fair, their technique does seem to work for them if they have an absolute iron discipline when it comes to the cutting phase.

It seems to me that IF works just as well and is much more workable as a long-term lifestyle, as opposed to months of being really cranked on lots of food and then grumpy as hell when the party ends and you have to cut.

I think the Minnesota Starvation Experiment is relevant in this discussion of "therapeutic overfeeding". In it, healthy lean men were starved down to approximately 5% bodyfat during 6 months, and then a rehab program of re-feeding to return to their normal body weights commenced.

What they found was basically that the higher the caloric surplus (up to 4000 kcal if I recall correctly), the faster they brought up their metabolism and temperature to normal, and the faster the psychological symptoms of starvation and hyperphagia were reversed.

It was also found that after 8 months (3 months controlled overfeeding and 5 months ad libitum), they had reached 100% of their normal body weight, but were at 140% of their normal body fat - so they initially gained way more fat than they lost during starvation. This fat disappeared during the following months though, and after 1 year of free feeding or so - most had almost normalized their body composition.

Now, I think it can be argued that this state of experimental hypometabolism that they induced through starvation actually has a lot in common with the normal situation of many failed dieters of today. Many have been on caloric restriction at least as severe as that in the study - for several years, not counting short breaks of overfeeding. Furthermore we subject ourselves far more to insanely intense exercise regimens, get far less sleep, rely massively on stimulants like coffee to keep us going still, and probably suffer from more social stress than before. In addition, many of us have been raised to a large extent on an atrociously nutrient-deficient diet of processed foods and shitloads of candy, which already leaves us more vulnerable to these stresses.

This would be seem to be supported by the fact that a low basal temperature is actually considered a normal state today, and that so many diseases of the diseases of civilization show a strong connection with chronically elevated cortisol levels.

Just wanted to add, I think fruit juice is also a culprit in obesity, maybe even more than soda and snacking. When I grew up (late 60s) fruit juice was a rare treat, often home made and only oranges or apples were used. Now people give juices to toddlers thinking it is healthy. People know that soda and candy are bad (does not stop them though) and often choose a worse alternative.

I tried overfeeding for a couple of weeks and gained about 6 kg (mostly fat I would say). On the plus side: my body temperature rose marginally. Now, 10 months after ending the overfeeding I still carry the extra fat with me. I can´t recommend overfeeding.

I think the weight loss prior to the leptin administration is critical. Depleted fat mass would probably suck glucose and fat out of the blood stream more efficiently. Triglycerides interfere with leptin signalling in the hypothalamus. Also, a person might have higher than normal levels of leptin when obese, but lower than normal levels after a diet. Most people can go on a diet and lose weight, but most fail to keep that weight off afterwards.

Lyle Mcdonald recommends carbohydrate "refeeds" to restore leptin levels when dieting. Recently on the leangains blog, Martin and Lyle answered someone's question about doing pretty much the same thing with fat. They ridiculed the idea, I think Lyle said it was "like a carb-up, but without any benefits," or something like that.

The present results demonstrate that long-chain fatty acids, the principal products of activated lipolysis, acutely inhibit insulin-stimulated leptin secretion from isolated adipocytes (Figs. 1, 2, 3, 4, 5, 6). We have previously shown that insulin-stimulated leptin secretion can be inhibited by a wide variety of agents known to increase intracellular cAMP concentrations either by stimulating its production at the adenylate cyclase level (catecholamines, lipolytic hormones, pertussis toxin, or forskolin), by inhibiting its degradation by phosphodiesterases (methylxanthines, imazodan, milrinone, or amrinone), or by mimicking its action (nonmetabolizable cAMP analogs; see Ref. 5). Without exception, all these agents stimulated lipolysis in the range of concentrations at which they inhibited insulin-stimulated leptin secretion. These observations, combined with the present results, strongly indicate that fatty acids mediate the inhibitory effects of lipolytic agents on insulin-stimulated leptin secretion.

The fact that concentrations of albumin similar to those found in plasma (4%) inhibit the effects of palmitic acid (1 mM) indicates that circulating fatty acids (the concentration of which varies at the millimolar level) have little influence on leptin secretion, at least directly (Figs. 1 and 3). This is supported by several in vivo studies in humans, which failed to demonstrate any inhibitory effects of fatty acids on plasma leptin concentrations (35, 37). It is more likely that an intracellular increase in fatty acids, generated in consequence of activated lipolysis, causes the inhibition of leptin secretion.---------------------------------

Niacin increases leptin levels. Niacin shuts down lipolysis temporarily. Eating fat leads to the dreaded ASP, and fat storage-- and temporarily decreased lipolysis, for a while more of the free fatty acids in the fat cells will be from outside of the cells, meaning that they will be accompanied by albumin-- which means they will not suppress leptin secretion. The ketogenic (high in fat, rather than protein) diet increases leptin levels. If you can manage to secrete leptin without elevating insulin at the same time, maybe there's a little bit less metabolic oversteering? Intermittent fasting? Eating less calories spread out over the day versus compressed into a smaller eating window-- I wonder what that does to leptin levels? Or barring that, leptin sensitivity?

Maybe I mis-spoke about the ketogenic diet needing to be high in fat rather than protein; would eating more protein make for free fatty acids entering the cell being more richly albumin-bound?

One more thing to blurt out-- it's the long chain fatty acids that suppress leptin. So what about coconut oil, or short chain fatty acids from butter and cheese or colonic fermentation?

allostasis, not homeostasis. the body tries to adapt to what it predicts it will need. i don't completely understand the concept, but it made sense to me when prof devany was explaining it on his old blog. he recommended a book about it, but i can't remember the name.

Just wading into the present discussion with: 'Lights Out: Sleep, Sugar, and Survival' by T.S. Wiley with Bent Formby PhD.

Yes, the name is for real. Norweigian. 2000, Simon and Shuster.

I read this last year and gave me plenty to think about. The chapters are 203 pages long. The endnotes are 93 pages long and the bibliography is 7 pages. Well, at least this gives an impression of something that has been researched.

Blue light from artificial light sources like televisions and computer monitors stimulates the pineal gland. Orange light at sunset is what our brains have evolved to neurtransmitterly respond to at the end of the day. Artificial light puts us into a 12 month summer.

The book is definitely worth reading. They've done an excellent synopsis of what goes on with neurotransmitters, and hormones when exposed to not enough darkness and too much sugar.

Possibly it could add valuable insights into what's going on with obesity and how it's not always a caloric balance.

I read today that 20 minutes of physical activity once per week (and that includes walking) is sufficient for mental health.........yeeehaw. Being the not activest individual at this time, it's nice to know. I keep regular sleep wake cycles, and eat mostly paleo. And a bit of booze which getting more bitty as time goes on.

I've always believed that 1 lb fat = 3500 calories was ridiculous during the classes I took at UB Berkeley in undergrad nutritional sciences.

Thank you for dispelling the myth so articulately. The calorie counters on the treadmill should be the next to go...

ItsTheWOOO,

I once had vitamin D deficiency as you had leptin deficiency. Good for you for diagnosing yourself and getting the hormone replacement that your body no longer can make. Your insights are always compelling! Over and over again it appears to me that so many of us young people (age 20-70s *haa* I use the term loosely) are 'damaged' excruciatingly deeply from decades of the S.A.D., lack of sunlight, excess grains/gluten/n-6 and complete deficiency of saturated fats and n-3 pufas and likely in utero hypothyroidism/hypovitaminosis D/n-6 toxic/sat-fat-deficient.

Were our mothers leptin resistant? Adiponectin deficient? Were we set up epigenetically and therefore out of our control?

I read Lights Out! a couple years ago on the recommendation of another. I really enjoyed reading it, but was very disappointed with what I later learned about T.S. Wiley and her "research". Yes, the book raises some interesting notions, but be sure to look up those endnote references for accuracy before your hang your hat on anything in the book.

Formby is actually Danish, btw, and T.S. Wiley, well, google her name, the phrases "wiley protocol" and "wiley watch", the wikipedia page on her, and her husband's Amazon book review responses and you'll see what I mean. I spent an evening or two following links on Wiley and came away with lots of questions and less faith in Wiley's "research" acumen. It appears that Formby and Wiley parted ways after they disagreed on the content in the appendix of their second book (on female menopause and hormones). Formby is the one who actually has a degree and academic credentials.

One valuable thing I learned after reading this book was to not assume a lot of endnotes means a book is well-researched or that the references support the claims (I'm not scientifically-trained, only married to a scientist ;-). But it seems having 1/4 or more of a book with endnotes can simply be a lot of puffery to lend an air of credibility.

the somewhat off kilter reason I mentioned how many pages are chapters and how many are not is because considering the length of the book, the amount of actual reading material is not very much.

I did check out the authors partly because, thanks for the correction, the Danish name in English sounds quite strange.

But we shouldn't throw out the baby with the bath water here. My point in bringing up the book is that there is more to good health than food. Sleep is crucial as well and our life styles are interfering with the quality of sleep we require. It's not just from this book but a person can find the information readily elsewhere that all the visual stimulation from excess illumination is preventing good or adequate sleep. The development of obesity due to hormonal and neurotransmitter dysregulation is not breaking news.

Stephan's blog post reminded me that there are other factors in weight gain and weight loss than just one sort of calorie or another.

I have read somewhere that insulin has anorexigenic effects on the brain. So someone who is insulin resistant might not react to insulin by decreasing appetite. This might be part of the reason why low-carb diets are more satiating, the brain responds to hormones indicating you ate fat and protein, but not carbs (insulin), so it makes you eat more because it thinks you ate less than you really did. What do you think of the idea? On the other hand I have read articles suggesting that insulin increases appetite.

Yes, I hope I didn't give the impression there was no value to the book. On the contrary, I find myself thinking about certain parts of the book often and I have recommended it to people, although with some caveats. I am far more mindful of my sleep habits these days, esp my tendency to be a night owl (too often in front of an electronic screen), and the multitude of tiny lights in my bedroom (I moved the router and cable modem to another room, too).

Nor do I think the only way to become expert in a subject is through advanced university degrees (I only have a Bachelor's degree but I think I've learned far more in the past few years on my own).

I would bet that it is High Fructose Corn Syrup and Fructose that has been buried in our food over the last 40 years is the culprit in screwing up our setpoints.

These two products are not recognized by our brain due to leptin resistance....and thus our fullness meter is not on...thus we continue to eat past our fullness point. Listen toDr. Lustig's lecture, Sugar: The Bitter Truth, on youtube.

The first time I read this page from Horn http://www.medbio.info/Horn/Time%201-2/carbohydrate_metabolism.htm

5 years ago, it was clear the havoc fructose can cause. The most stunning part was not the bio-chemistry itself, but the fact that it is old. Horn is one of the standard books used in biochem in Universities in Europe (may be in the US as well). So this is not controversial in the least. But nonetheless, mainstream medical teaching does not recognize the danger of fructose and one can still buy 'diabetic' sugar products where glucose was replaced by fructose, given to people who were made ill by that same product.I heard recently in an interview (at Jimmy Moore's I think) that the assistant of Walter Willet (forgot his name) who is one of the most prominent researcher in obesity and nutrition didn't know 2 years ago that sucrose was half fructose, half glucose. This blew me away, even I before I got interest in this subject, befor access to the Internet, as a simple geeky computer guy) knew that 20 years ago. That's imho a sad indiction of the state of (medical) science.

This might only be me, but since I've had a decade of working with people for fat loss, I've noticed those who lose best allow themselves plateaus along the way. I have a client now who has lost 30lbs, but after the first 15 he intentionally stopped trying to lose and focused on maintaining this level for 3 months before intentionally trying to lose fat again. In this fashion he's noted that by the 3rd month it was "nothing" to keep his weight at that target, while it was a bit challenging at the start of the 3 month period.

My point is, or really perhaps my wonder is this: I suspect that set-point can fluctuate within a fairly large range. Given the hormonal implications of obesity, or over-fatness in general, might there be a delay period of adapting to a given body fat? In practice I've found this to be the case.

> … research has not identified them to my knowledge, at least not in humans.

There is a lot of empirical evidence, although scattered, that consumption of refined carbohydrates and sugars above a certain threshold leads to an imbalance in the secretion of hormones that regulate fat storage and mobilization. Among the hormones involved in this imbalance, insulin seems to stand out.

I'm interested in your story about the plateau periods because this is what happened to me (the plateau was over 6 months), and I noticed on Richard Nikoley's site that he too was initally losing, then stalled, then woke up to find he was his goal weight. This has also happened with various friends of mine.

I guess you could say that the last 10 to 20 lbs seem to frustrate us for some time, then disappear almost overnight. Is this the setpoint readjusting, or we're just simply getting used to eating less and didn't notice because it was so gradual?

Kurt Harris also talks about baseline insulin, which is our normal insulin level. Skinny people can eat all they want and not get fat because baseline insulin is inherently low, so it has much farther to go to be "high" when eating.

Is out bodyfat setpoint just our baseline insulin? Are the swings and stalls in fat loss due to baseline insulin stabilizing and then readjusting to a lower level again?

It's so interesting that you said that. Walter Willet stated in the Sept 2007 Harvard Letter that n-6 pufas are similar to monounsaturates in health 'benefits'. Is he nuts??! Time to fatten up our diet to 40% with n-6 pufas and monounsats (keep sat fat at 8% OMG!!).http://www.health.harvard.edu/newsweek/Time-to-fatten-up-our-dietst.htm

The AHA is promoting higher n-6 intake of 5 to 10% for 'cardiovascular benefits'(Circulation. 2009;119:902-907.) It is the most absurd thing I have read this year. Mozzafarian is at Harward also (sadly).

When thyroid or estrogen (HRT or oral contraceptives) or vitamin D are giving to deficient inviduals, blood or salivary levels are not drawn for 4-8wks later to allow for optimization in the blood. It takes time for the hormones to exert DNA translation, protein synthesis, receptor assembly and to posttranslational protein effects.

When I do a big jog (like 1-2 hrs) I don't lose weight/BF until 1-2 wks LATER. I've tried to figure this out but I think it is related to the late effects of adiponectin and other hormones. When I stop fish oil, I gain wt from higher insulin resistance 1-2 wks LATER. When I stop vitamin D, I gain weight 2-4 wks later. BTW, I drop body fat more easily when my estrogen is high (e.g. prior to ovulation) -- not that I am recommending for any men out there *ha*.

Stephan,I hope that you include in your future explanations the observations from fecal transplants between fat and lean individuals. Switch their gut flora and the lean gain weight while the fat lose weight. The gut flora dominate the metabolism. What does this say about set points?

Since the topic of fat loss plataeus came up, it's rarely a strictly linear process past the 8-week mark. Stalls followed by catch-up weight loss often occurs after this point. Clients might "stall" and come in at the same body weight two weeks in a row, only to drop 4-6 lbs seemingly over night on the third week. It's an oddity not yet explained or understood. Lyle McDonald termed it the "whoosh" phenomenon.

Oh, you mean Lyle doesn't have the science on that sorted out enough to call everyone a moron and idiot who doesn't know what he's talking about?

Amazing. Wonders never cease.

Well, I've taken off 60 pounds through fasting high intensity workouts. My favorite are at about 24 hours (I've done up to 36), where I can bring on and get rid of hunger at my whim, though varying intensity, particularly in leg presses & deadlifts.

But no matter. Nobody can teach Lyle anything, for he "knows" everything.

In a recent study of the effects of a 12 week ad libitum carbohydrate restricted diet on overweight men in which carbohydrates were 13% of energy intake (pubmed ID 16674818), caloric intake was spontaneously reduced by 30% which resulted in a 7.5 kg weight loss and 20% reduction in abdominal fat.

Apparently the "set point" of the participants was reset by increased consumption of "nutrient dense" foods and by elimination of refined carbohydrates that were not only nutrient deficient, but also high in trans-fats (which were reduced by 38%) and refined vegetable oils.

"I've followed your progress (congratulations!) and was wondering if maybe you could recount what happened to you, in terms of the "stalls and restarts" of fat loss."

Well I didn't begin eating paleo until about 6 months or so into my program of two 30-minute intense weight training sessions per week. I was losing about 1 pound per month.

Once I went paleo in around Oct '07, I began losing about 2 pounds per month and then I incorporated the fasting Jan '08 and was doing two 24-30 hour fasts per week in advance of the workout and then would go a couple hours after the workout before breaking fast. Fat loss was so rapid then I couldn't tell you -- but I was also getting stronger too, which was interesting.

At any rate, I began at around 235 pounds (5'10) and the first significant stall was at 210. I meandered 210-215 for probably 3 months, then rapidly went down to 200 in a matter of a couple of weeks, then stayed there for 4-5 months 200-205, then wham, down to 190, then 190-195 for about three months and then bang down to 180. I was there only about a month, then 175, and that's where I am now, 175-178 for a couple of months.

My fasts are more random now, less regimented, and because I'm just never hungry before noon I've been doing more of a daily eating window thing, noon to 8m, roughly and it seems quite agreeable.

Many thanks Richard. The fact that you're never hungry now should not be overlooked. The lower your hunger, the lower your baseline insulin, as far as I understand. This mimics my experience almost exactly, though my fasts are shorter than yours (22 hrs tops).

This has a snowball effect, I think, as now even when you pig out, you get fuller faster and your insulin doesn't rise as much as it did before. Therefore less cumulative fat gain over time...

Apparently the "set point" of the participants was reset by increased consumption of "nutrient dense" foods and by elimination of refined carbohydrates that were not only nutrient deficient, but also high in trans-fats (which were reduced by 38%) and refined vegetable oils.

If the "set point" were actually reset by removing the refined carbs etc. then the subjects should have been be able to eat whole grains and tubers without putting the weight back on - which is presumably not what happened in the study.

Many low carbers believe that their way of eating is "the natural way" .. whereas Stephan (and Gary Taubes) are likely to view it as a (perhaps) harsh way to circumvent the damage done to metabolism by a Western diet.

Yes, leptin is clearly critical. It's not just an issue of leptin levels in the blood though, there's also the issue of leptin sensitivity. In your case, you were leptin sensitive but just produced too little leptin, so adding leptin worked great. But most people are leptin resistant, so the strategy won't work for them.

Hi Ned,

Yes, I would be very surprised if refined carbohydrates, particularly sugar and white flour, were not involved somehow.

Hi Art,

I'm definitely going to be touching on the role of the gut in all this. As for fecal transplants, are there data in humans yet or is it all in rodents at this point?

Hi New York,

I don't think I'll be covering that hypothesis, actually. I've drifted away from it over time. It's not that I'm sure it's false. It's just that there isn't any direct evidence of it. The other problem is that white flour barely contains any WGA, so you'd expect it to be a problem mostly with whole wheat.

I learned - the hard way - that reducing my calories too much leaves me sick and feeling terrible. I was 16, trying to take control of my health for the first time, and ended up more than a little overzealous. I'd do heavy lifting at least three times a week, and ate very little. Whenever I did a food log, it came up to roughly 1,400 calories a day, a significant amount of that coming from protein. On 1,400 calories a day with serious exercise, I lost about 10lbs/month for 4 months. At which point my thyroid died. No more gains in the gym, chronic injuries, hair falling out, winter coats in summer, the works.I made that mistake a couple more times until I realized that gluten is evil incarnate, and I can still lose weight while eating heroic amounts of calories, just more slowly. Turns out if I eat "real food", I end up at 3,000-4,000 kcal a day and a ton of fat. If I just eat until I'm not hungry, eventually I'll get full on a lot less, about 2,200 kcal.

That takes time, though. Most people are in a hurry. For me, the good news has been that if I focus on how I feel, I DO lose the weight. About 50 pounds in the last year, although I have at least 100 to go. Learning how to eat so I *feel good*, learning how to cook well, and taking care of my poor half-dead thyroid seem to do okay. I just have to be careful to eat enough, or else I'll backslide into eating junk. My skin, energy levels, and mental health all suffer much worse and much faster than I gain the weight back.

That, and intermittent fasting rocks. I've always naturally wanted just one large meal a day, so it works well. I feel amazingly alert on days I don't eat. Never really understood how people get by on eating lots of little meals a day. Granted I was the little kid eating sticks of butter, and margarine or shortening (eew, I know) when butter wasn't available.

Regarding epigenetics, my mother was one of the people that bought in to the super-low-calorie/low fat paradigm. She was put on a 600kcal/day shake diet, then has some part of her gastric system removed at some point before I was born. I've been obese, crazy, covered in skin rashes and infections, and had stomach problems since I was an infant, so there may be something to it. Especially since I'll gorge on anything with fructose or gluten in it, and be unable to stop, short of being beaten.

Yay modern foods. Sick, bitchy, rashy, depressed, fat, and stuck in the bathroom about sums them up. I still eat butter straight, but only the grassfed stuff. Because it's tasty.

Ah, rambling! Anyway. There is one thing I can speak to with certainty, and that is that the "Randy" person that exhibited baffling behavior here recently took on a style of interaction that I've seen before with trolls. It's difficult to say whether that was the case or not, because troll folk like to copy real behaviors to annoy everyone, but it's pointless to talk with a kind of person that acts like that. The goal is to (mis)quote authority figures, independent of context, to superficially score a "victory" in a debate. No actual discourse happens. Ever. There will only be a continual farming of quotes. If people decide not to respond to it, it becomes harmless clutter that can be amusing in context.

Just thought I'd mention that the pattern isn't uncommon, and that you probably did the right thing, Stephen. If someone under a different account does it, you can bet it's the same person, trying to get a rise out of people. Good luck.

Have any of you doing the intermittant fasting ran into problems with gallstones? I have had some problems recently, and I saw that skipping meals was a risk factor. I have gone long periods where I would eat only one big meal a day, but I don't how big of a factor that played.

Some of the core observations were made by Djurhuus, predominantly looking at type one diabetics. While he accepts that elevated insulin causes Mg loss in the urine, hyperglycaemia appears to be the main drive. This gets to the point where you can correlate magnesium deficiency with HbA1c in type one diabetics. As an elevated HbA1c suggest relative insulin deficiency in this group, then hyperglycaemia appears to be the problem.

It's open to speculation whether Mg deficiency is a specific cause of metabolic syndrome or a result of the hyperglycaemia associated with it, but there is undoubtedly a clear association between the two.

Once you have mangled your magnesium status you appear to be wide open to calcium based stones.

In fact metabolic syndrome might be enough to trigger calcium stone formation on its own, especially if you are not thinking about magnesium status...

[...]

What happens when you have metabolic syndrome and suddenly start living within the carbohydrate limits imposed on you by that syndrome? When you suddenly become normoglycaemic and norm-insulinaemic?

I doubt any of us starting out on low carbohydrate diets gets an MRI done to check if we have renal stones before we begin, just on the off chance. A sizeable number of the population drawn to low carbohydrate eating might well carry asymptomatic renal stones. The stones then begin to dissolve once people stop peeing their bones down the loo. How many will convert a large asymptomatic renal pelvic stone to a smaller stone which can enter the ureter to begin its agonising journey to the bladder?

You think low levels of leptin are not relevant, only low leptin sensitivity?

Common sense suggests to me that they both ought to play a part. We know that your body fat controls your leptin production, so decreased body fat == decreased leptin production. Sensitivity is orthogonal, I think. I am not an expert however!

Besides an autoimmune attack on the gall bladder caused by things like wheat, I have also heard that gall bladder problems can be caused by not eating enough fat. Bile in the gall bladder backs up when it is not released for digestion of fat and stones can form. Then if a large quantity of fat is later consumed, the gall bladder tries to squeeze out sludgy bile and stones and the person has what they call an "attack."

Many people switching from a low-fat diet to a high-fat diet complain of gall bladder problems at first.

I'm getting in rather late for this discussion but I can offer one hypothesis why overfeeding for a period might lead to a higher set-point.

Spalding (2008) found that fat cell count in humans was relatively fixed but weight gain (or loss) was predominately in changes of the volume of fats stored per cell. However, obese individuals did have significantly more fat cells.

However, if you overfed someone by 50 % by calories (quite a lot!) then perhaps that would provide a great enough signal to exceed whatever threshold that is required to induce mitosis in fat cells.

So fat cell count may be directly related to circulating leptin levels, which would make a fair amount of sense. As one gets more obese, the ratio of lean to adipose tissue decreases, so if each adiocyte is releasing a more or less constant amount of leptin based on 'fullness' then an obese individual should have higher circulating leptin levels, and be leptin resistent thanks to overly full fat cells.

Jequier (2002) states that leptin does down regulate CRH, so it's actually down-regulating cortisol production. In a natural setting that would tend to lead to weight loss but eating of a diet high in inflammatory agents would swamp that signal, leading to obesity.

What is the link between leptin and TSH? Jequier states that thermogenesis is increased (via TSH). However, TSH is produced in the pituitary, which granted is right next door, but I'm not aware of an analogue for CRH->ACTH for TSH. Have you ever seen such a hormone? Can the neurons of the hypothalamus directly stimulate follicles in the posterior pituitary?

Stephan I think you'll enjoy the Jequier paper just for the cognitive dissidence.

Something that has been bothering me (im a mathmatician) about the "set point" idea is that if its purely related to the number of white adipose cells. Let me explain.

First some basic assumptions...1) Under normal circumstances, all white adipose cells are identical2) white adipose cells secrete leptin in a manner that is directly proportional to how much fat is stored in it3) After a meal, fat is transported to all white adipose cells in equal distributions and AT THE SAME RATE.

Assumption 3 has depressing consequences. If you accept it, it implies obese people who lost weight have their set point much raised becuase they have more white adipose cells.

For an example of what im talking about, lets pretend a white adipose cell needs to be 50% full before it starts secreting leptin.

A former obese person with 100 white adipose cells will need to eat MORE than a normal slim person with 75 white adipose cells before each cell gets 50% full BECUASE of assumption 3.

With the former obese person needing to eat more just to get the leptin feedback loop working normally you can instantly see how the set point is naturally raised.

On a side note, Ive been reading a bit about how uncoupling proteins are suppose to increase leptin sensitivity, and ive recently begun taking quick ice cold showers before going to bed, results in soon!

It may be depressing but it does appear to be the truth. Reducing fat cell count should take years of effort, based simply on the average lifespan of ten years.

Fat in general is not distributed uniformly. Peripheral fat deposits (under the skin and in-between muscle spaces) is considered much less hazardous to health, if it is hazardous at all. In comparison, fat inside and clustered around vital organs, especially the liver, is called central obesity and is a much stronger risk factor for metabolic syndrome and diabetes.

Fortunately while formerly obese individuals may have more fat cells than those who were lean adolescents that doesn't necessarily mean that they are less healthy. Leptin and insulin sensitivity of adipose tissue is more likely to be of cell fullness than cell count.

Mikael:

I am getting deeper and deeper into inflammation, autoimmunity, and endocrinology (particularly neuroendocrinology). It's quite the rabbit hole. I find it quite fascinating how many people seem to present sub-clinical symptoms of autoimmune endocrine diseases for example. How does one 'sort of' have an adapted immune system response. So many questions in this area.

One point of interest is how genistein, a polypeptide found in soy, binds to thyroid periodixase (TPO), the enzyme with iodinates tyrosine and essentially builds T4 (Doerge, 2000). The binding of genistein to TPO is inhibitory, resulting in lower T4 levels. The natural consequence of this is the hypothalamus and pituitary are going to have to further pump up the TSH levels to try and compensate.

Do you think disrupted folding/transport of leptin might also be induced by dietary mechanisms, too? (In addition to interference with leptin receptors, i.e. leptin resistance in a more stricter sense?)

Similar issues with fluoride, if I'm not mistaken. Speaking of hazardous food and health -- have you read Barry groves excellent book "Trick and Treat: How 'healthy' eating us ill"?

And on the subclinical (subchemical, really - clinical is the only thing it is!) hypothyroidism: during winter, extra-thick socks, a sweater, jacket, beanie, mittens is normal, right? Well, try indoors. At 25C. Whack. :-/ Lack of sunlight (and disturbances in associated signaling substances) might affect things, there's really not much sun here in Sweden at this time of year.

Any idea on the high prevalence of these health issues in recent years? Like, the major player if kept to just one or two factors.

I'm pretty sure that idea is based on a misinterpretation of the recent paper by Ozcan et al. in Cell Metabolism.

They restored leptin sensitivity using "chemical chaperones" that reduce protein misfolding in the endoplasmic reticulum (ER). The chaperones didn't influence the folding or transport of leptin. What they did was reduce ER stress, which causes leptin resistance. When the ER is full of misfolded proteins, it initiates a cellular stress response that shuts off hormone sensitivity. The chaperones reversed that.

It is an interesting finding. Being able to restore leptin sensitivity in humans would be huge. I do think it's weird that they had to inject additional leptin along with the chaperones. If it was reducing leptin resistance so well, there should have been enough leptin around to take care of the job. It must have only partly restored sensitivity.

"Hopefully one day obesity will be dealt with solely by endocrinologists!"

mmmmmm.... the same endocrinologists putting fat people on 800 calorie diets? (That's what happened to an obese friend of mine recently and her endo told her that's what she needed to do.) I hope not! :)

Gotta say, though, this "grazing" mentally really bugs the heck out of me. Recently Mehmet Oz was promoting this. He also promotes eating whole grain bread as a way to combat hunger (honestly?) along with fructose juice "fasts" to detoxify the liver. Yup, detox your liver with fructose. Unbelievable.

Stephan,

There is a paper or two referenced in the paper you mention indicating that transport of leptin across the BBB can be a problem. I don't know anything about this but it sounds interesting... I don't know enough of the dietary biochemistry to be informed enough about how these problems might be caused by diet, but I was just wondering if there may be ways in which it is (just like the hypothesis about lectins binding to leptin receptors...)

That describes my attire a few years ago, except I am in "sunny" San Diego and I dressed like that practically year round. Everyone else was wearing shorts, tank tops and flip flops. My doctor's nurse always joked about my 96°F temperature and cold hands. It was a huge relief to finally take thyroid hormone and return to a reasonably normal body temperature and a seasonal wardrobe. I used to joke that I wished for menopausal hot flashes!

Even now that I'm taking taking thyroid hormone (whether synthetic or natural dessicated) I have some hypothyroid symptoms return as the days get shorter in August & September, necessitating a small dose adjustment up, especially T3 (I don't think I convert T4 to T3 well). In late spring my dose is adjusted down a bit. Summer is my best time of year.

I think I began to be hypothyroid when just before I turned 30 (lots of acute stress for a few months, bad high carb, high omega 6 diet, then a sudden switch from always skinny & boyish figured to a more rounded figure and just slightly overweight). But the hypothyroidism symptoms began to increase after I became very strict about sun protection after moving to San Diego and having a basal cell cancer removed from my nose. I'm sure I became quite Vit D deficient, too (I was so very *good* and compliant with the high SPF sunscreen, midday sun avoidance, and covering up).

The hypothyroidism symptoms became even worse in 2005-6 after about a year on a low carb diet while consuming low carb processed products made with added gluten and soy protein (now I know I make antibodies to gluten and soy). By that time I was also perimenopausal and very low in progesterone (actually a lot of my hormones were unusually low). Despite classic hypothyroid symptoms like infertility, low temp, no perspiration at all, weight gain, a rising TSH in the upper half end of the ref range (but still "normal" by the outdated lab ref range, which was revised about a year ago after I spoke to the lab supervisor and informed him about the latest AACE and NACL recs!), no diagnosis. Sigh.

Monica, I'm not a fan of low-calorie diets. This 800 calorie diet your friend was put on may be okay if done for a few weeks then up the calories for a week and back down to 800.Maybe for someone very obese it may be okay??

It was a few years back. He was actually making a good point that many overweight people would benefit from eating eggs (rather than a higher carbohydrate meal) to keep insulin down. But he said it would be great if they were cooked in corn oil!

To Willett's credit, he admits that eggs are perfectly healthy. But saturated fat is still not healthy, of course...(hence the corn oil!...sigh)

Willett is a strange one. I have ready his book The Fertility Diet. Apparently, a lot of his recommendations are supposed to be based in the Nurses Health Study... problem is that the findings of that study (those studies, rather) don't really support the fertility recommendations in his book. There's a heavy mixing of of information from the Nurses Health Study (which is epidemiological, anyway) and conventional wisdom.

I'm re-posting this study from my earlier comment because I think it's important, and may have been over-looked due to my blabbing on. And I think it has some connection to your comment about how much fat needs to be stored in a fat cell before it releases leptin.

http://ajpendo.physiology.org/cgi/content/full/285/3/E521

What the study shows is that leptin, rather than being directly increased by fat storage, is decreased by lipolysis. Like a dead man switch. Newly present fat from circulation does not suppress leptin release, but just-released fatty acids from the fat cell itself do. Somehow it seems less hopeless this way. It's as if the body isn't trying to achieve a particular level of fatness, it's just avoiding dumping more fat out into the system when the pipeline is already full.

"What caused the system to defend a high fat mass?Is it possible to reset the fat mass setpoint, and how would one go about it?" Stephen, I think you have incisively stated two very timely questions. If you come up with a cogent answer I promise I'll buy your book, sing your praises, nominate you for knighthood, and bear your children. Well, maybe 3 out of 4. Heck, if you are right, the world will forget all about Gandhi, Einstein, Tutu, Newton, and similar pretenders.That said, thanks also for the fascinating comments, some of which I kind of understand.

'Is it possible to reset the fat mass setpoint, and how would one go about it?'

Exercise sensitizes leptin receptors and/or aids leptin transport across the bbb. Other than that, there is nothing in the scientific litterature to suggest you can do anything to adjust bf setpoint downwards - only upwards. Sad but true.

In response to my post of Jan 3 about a study on carbohydrate restriction which found a 30% spontaneous reduction in caloric intake after a 12 week ad libitum CRD, New York said:

"If the setpoint were actually reset by removal of refined carbs etc. then the subjects should have been able to eat the grains and tubers without putting the weight back on - whereas that was presumably not what happened in the study"

Your presumption is incorrect. The study included no such conclusion. It is my guess that those on a carbohydrate restricted diet would not gain back significant weight if tubers and grains were consumed.

New York also said:

"Many low carbers believe that their way of eating is the natural way, whereas Stephen (and Gary Taubs) are likely to view it as a (perhaps) harsh way to circumvent damage done to metabolism by a Western diet".

I am not a advocate of carbohydrate restricted diet, but I believe that it is "way less harsh" than the "prudent diet" advocated by the Willet and the low fat crowd. It results in reduced inflammation, reduced athrogenicity of LDL particles, weight loss, and improved gut flora. It does not address the problem of excess intake of refined vegetable oils, and may not provide adequate fat soluble vitamins or fiber.

what about this."With respect to the long-term sustainability of this regimen, it may be noted that author M.F.M. has followed this regimen for 12 years and, at age 56, maintains a body fat under 5%, having lost approximately two-thirds of his initial body fat. Presumably, as body fat stores decline and fat becomes less available for oxidation, there will be a compensatory increase in calorie intake (and fat in-take) during meals, such that body fat content eventually plateaus at a considerably reduced level."

Stephan – I disagree that leptin resistance figures in obesity, and I think that general anti-inflammatory approaches help obesity because inflammation causes hyperinsulinemia and insulin resistance. It is false to attribute this benefit to a reduced leptin resistance, which remains to even be proven.

I’ve researched this extensively, and leptin deficiency after massive weight loss is the rule and not the exception, particularly for women (who are leptin dependent and require a higher leptin than men do). If I were so atypical, why do laboratory tests show that dieters are leptin deficient after weight loss? (deficient meaning that if you compare a non dieted individual of equal stats to a dieted one, the dieted individual has far less leptin than the non-dieted one).

Why do recent studies suggest that leptin replacement after weight loss can help maintain weight? A pilot study showed brain activity in response to food normalized when subjects were treated with leptin after weight loss.

The company who manufactures the leptin I am taking (for hypothalamic amenorrhea from weight loss induced leptin deficiency) is now announcing they will investigate leptin as a treatment for the post obese:

http://www.bloomberg.com/apps/news?pid=20601124&sid=agme3MESlQ5k

I secretly like to think my blogging and participating in their prior clinical trials may have influenced this shift, but I realize that is probably grandiosity lol.

Again, I want to reiterate that reduced inflammation is going to be a boon to the obese, but this is not mediated through leptin, it is mediated through insulin resistance/sensitivity.

Robert McLeod – CRH/ACTH actually tend to suppress appetite. These hormones raise neurotransmitters and increase mood/activity/energy. Second, they are often shunted into MSH which is very appetite suppressant. The end products of adrenal gland function – glucocorticoids – these raise appetite quite a lot, but having higher CRH/ACTH/MSH does not translate into having high glucocorticoid levels. Not all the time, anyway. The “atypical depression” syndrome is a condition of supersensitivity to cortisol and excessive suppression of CRH/ACTH as a result.CRH/ACTH aren’t bad in of themselves, and they are stimulant hormones which actually promote thinness.It’s the excessive response/release of adrenal hormone that causes fatness and it is not always logically true that a higher CRH output leads to this state of affairs.

The link between leptin and TSH is that leptin increases TSH level and also enhances peripheral conversion of T4-> T3, via the sympathetic nervous system.

Kindke – I have come to similar conclusions independently. Adipocyte hyperplasia causes secondary leptin deficiency after weight loss. The minimum fat mass of an obese individual is always going to be higher, as a sort of “scar” from prior hyperinsulinemia. This is especially true if hyperinsulinemia occurs during childhood and puberty, when fat cell numbers are sensitive to development. People who gain weight later in life may find it easier to lose it because they are more of an issue of hypertrophic adipoicytes, whereas people who have been obese from childhood have a great deal of hyperplasia as well. Thus, extreme vulnerability to compensatory leptin deficiency when fat is depleted by carbohydrate avoidance and insulin reduction.

Yes, your conclusions are probably correct. Unfortuantely.

The good news is, the people at amgen, who make amylin/ synthetic leptin have finally realized that leptin deficiency is a major deterrent to weight maintenance in the post obese. (I narcissistically like to believe my participation in leptin trials helped them come to this conclusion, lol! I am one of a handful of women in the trial and I am the only woman involved who is post obese/leptin deficient as a result).

I look forward to the future where the post obese are treated by endocrinologists with replacement leptin, so as to restore/maintain normal endocrine/metabolic functions even after body fat depletion and existing with numerous hypotrophic fat cells.

The best “lifestyle” intervention for leptin deficiency that I have observed is adequate sleep. While this won’t actually treat leptin deficiency, it is true that leptin deficiency is compounded/exacerbated by our tendency to dodge sleep. This won’t have much of an effect for people with adequate leptin, but for a post obese person skating the edges of deficiency, sleeping more can have a huge benefit.

It is better to modify the thrifty gene hypothesis to state that the body tries to defend its highest fat mass. The body tries to avoid starvation. Our tendency to store fat is an evolusionarily conserved mechanism to fend off starvation

Low sunlight and low neurotransmitters make us fat because this tends to occur before winter and lean times nutrient wise.Our fertility is tied up in the seasons (e.g. melatonin suppressing reproduction somewhat to entirely depending on species) for similar reasons. People become hungry in the late fall and metabolism worsens. The intended goal is to store fat for winter.

The body is not trying to become fat and “hold on to nutrition”.Rather, we have genetically evolved to live by the sun, to live by seasons, and during some seasons we tend to hold fat and others we tend to lose it.The body tries to prevent starvation.

The body, however, has not evolved to understand obesity is even possible, so the body is a hapless fooled victim when it attempts to defend insulin-mediated obesity.

The body has only evolved to “defend fat mass”, it has not evolved to recognize obesity as even possible.

When the body confounds dieters who eat low carbohydrate diets and successfully lose weight with leptin deficiency and it sequelleae, the body thinks it is preventing starvation.It does not know about “hyperinsulinemia mediated adipocyte hyperplasia”.It has no idea it is possible to be too fat. Our genes were selected and created 1) prior to an abolishing of the seasons via constant light and temp…2) prior to constant high glucose diets, prior to low grade subtle metabolic assaults from technology & stress mediated sleep loss, 3)prior to low grade chemical exposure…

The body thinks “all body fat is good”. It does not know it is even possible to become three times a healthy size, it doesn’t know that hyperinsulinemia can render people immobilized from obesity, it doesn’t know hyperinsulinemia can reach a point where women can become infertile from PCOS, so on.

So, the thrity gene, as I see it, is not bunk. Clearly, we have genetic programs which tend to defend our body weight and store body fat.

But, this does not mean to say the body actively TRIES to make us obese… it is more accurate to say that our environment plays havoc with our anti-starvation and seasonal detection/adaptation genetic programs, incidentally producing “an endless fall” where we are stuck in an interminable loop of fattening, with no famine on the horizon.

I wonder if you have read or have any thoughts on the Simeon Protocol which uses HCG to, in theory, get the hypothalamus to tap in to the body fat to supplement a very low calorie diet and then uses a stabilization and maintenance period to effectively re-establish the set point at the new lower weight. It seems a large number of people are having great success losing weight and then keeping it off using this protocol.

This is something they don't tell many diabetics, and seemingly no diabetic educators.

A normal person can eat a hundred or more grams of carbs or do a whole bunch of exercise, and that 5g glucose in the blood hardly varies, because the glucose-stashing mechanism (beta cells-insulin) and the glucose release mechanism (alpha cells-glucagon-liver) are finely balanced.

That balance only has to be a bit out for the BG to double - that's only another 5g glucose in the total blood volume. Part of what breaks with insulin resistance is the phase relationship, so the insulin is chasing the glucose, then pushes it down and this will either cause a liver glucose release, or hunger, or worse, both, and it's easy to end up rollercoastering.

SOP is for diabetics to be told to eat 45 - 60g carbs for three meals and 15 - 30g carbs for three snacks in between so it's easy to see how this rapidly worsens the process - even if the meal "only" doubles BG, the reduced insulin action (IR) will just be knocking this back down before the next bolus of carbs arrives and the systems never get back into phase.

There's a lot of paddling going on under the water just with this one control circuit. Add in all the other circuits including leptin and leptin resistance and it doesn't make a great leap of the imagination to see that the circuits only have to be slightly dysfunctional for the effects of one broken bit to knock on to the others.

Of course NOT eating so many carbs that the glucose peak overwhelms the insulin is a good plan, and this logic would apply to whatever overwhelms the leptin circuit, etc.

especially read the papers Gys refers to, there are functions in other species which *should* still work in humans but get broken. IMO the connection between fat storage and migration may be more evolutionarily apt than fat storage and food shortage. We wouldn't have sat around and starved, we'd have gone out and hunted/gathered something and if we had to go a long way to do this the fat would have been ideal fuel.

About Me

I'm an obesity researcher, neurobiologist, and author. In addition to my research, I enjoy synthesizing and communicating science for a general audience. I have a BS in biochemistry (University of Virginia) and a PhD in neurobiology (University of Washington).
Whole Health Source is a free resource for anyone who loves the science of health.

Copyright 2008-2013

Please feel free to reproduce the contents of this blog, on the condition that you:

1) Attribute the work to me

2) Provide a link to the page where you found it

3) Do not use it for commercial purposes

Financial disclosure

I am a co-creator of the Ideal Weight Program, and I receive revenue from the sale of this program.

In addition, I am registered as an Amazon affiliate. I may receive a small commission on the sale of some of the books I review, or other products sold through Amazon.

Disclaimer

This blog is a compilation of my opinions. It's not advice; it's information that you can take or leave as you please. I don't intend it to replace professional medical consultation or treatment. Your health is in your own hands.